Synthesis and evaluation of (±)-dunnione and its ortho-quinone analogues as substrates for NAD(P)H:quinone oxidoreductase 1 (NQO1)

Jinlei Bian; Lili Xu; Bang Deng; Xue Qian; Jun Fan; Xiuwen Yang; Fang Liu; Xiaoli Xu; Xiaoke Guo; Xiang Li; Haopeng Sun; Qidong You; Xiaojin Zhang

doi:10.1016/j.bmcl.2015.01.057

Synthesis and evaluation of (±)-dunnione and its ortho-quinone analogues as substrates for NAD(P)H:quinone oxidoreductase 1 (NQO1)

Bioorg Med Chem Lett. 2015 Mar 15;25(6):1244-8. doi: 10.1016/j.bmcl.2015.01.057. Epub 2015 Jan 31.

Authors

Jinlei Bian¹, Lili Xu¹, Bang Deng¹, Xue Qian¹, Jun Fan², Xiuwen Yang², Fang Liu¹, Xiaoli Xu¹, Xiaoke Guo¹, Xiang Li¹, Haopeng Sun¹, Qidong You³, Xiaojin Zhang⁴

Affiliations

¹ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
² Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
³ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: youqd@163.com.
⁴ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing 210009, China. Electronic address: zhangxiaojin@outlook.com.

PMID: 25677663
DOI: 10.1016/j.bmcl.2015.01.057

Abstract

Natural product (±)-dunnione (2) and its ortho-quinone analogues (3-8) were synthesized and found to be substrates for NQO1. The structure-activity relationship study revealed that the biological activity was favored by the presence of methyl group at the C ring and methoxy group at the A ring. The docking studies supported the rationalization of the metabolic studies. Deeper location in the active site of NQO1, interactions with hydrophobic pocket and C-H…π interactions with the adjacent Phe178 residue contributed to the better catalytic efficiency and specificity to NQO1. Cytotoxicity studies and determination of superoxide (O2(-)) production in the presence and absence of the NOQ1 inhibitor dicoumarol confirmed that the ortho-quinones exerted their antitumor activity through NQO1-mediated ROS production by redox cycling.

Keywords: Antitumor; Dunnione; NQO1; Natural product; Reactive oxygen species (ROS).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Catalytic Domain
Cell Line, Tumor
Cell Survival / drug effects
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Humans
Kinetics
Molecular Docking Simulation
NAD(P)H Dehydrogenase (Quinone) / antagonists & inhibitors
NAD(P)H Dehydrogenase (Quinone) / metabolism*
Naphthoquinones / chemical synthesis
Naphthoquinones / chemistry*
Naphthoquinones / pharmacology
Quinones / chemistry
Reactive Oxygen Species / metabolism
Stereoisomerism
Structure-Activity Relationship
Substrate Specificity
Superoxides / metabolism

Substances

Enzyme Inhibitors
Naphthoquinones
Quinones
Reactive Oxygen Species
Superoxides
dunnione
NAD(P)H Dehydrogenase (Quinone)
NQO1 protein, human